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Home , Hyperkeratosis, Lupus erythematosus

International Journal of Pathology; 2005; 3(2): 76-80

The Value of Individual Microscopic Features in Diagnosis of Cutaneous Erythematosus (LE)

Ambreen Moatasim and Anwar Ul Haque

Department of Pathology, Pakistan Institute of Medical Sciences

Objective: The objective of this study was to determine the frequency-based value of various histologic features encountered in biopsies evaluated for LE. Study Design and Setting: This descriptive study was performed over a period of one year at Pathology Department of Pakistan Institute of Medical Sciences, Islamabad. Subjects: The total number of cases was 50, selected through convenience non-probability sampling. Methods: A histopathologist and several dermatologists evaluated each case of skin biopsy together on multi-head microscope and TV monitors and combined diagnoses were made. Later on all slides were reviewed by a senior pathologist. A criterion was fixed for examining each slide. 12 histologic parameters were studied in each. Each of these parameters was further graded into nil, mild and prominent. All the data was entered into SPSS and frequencies calculated. Results: , basal cell damage and damage were present in all 50 (100%) cases while epidermal in 49 (98%) and periappendigeal and perivascular inflammation were seen in 48 (96%) cases each. Epidermal atrophy was prominent in 90 % cases, while basal cell damage, collagen damage, periappendigeal inflammation and hyperkeratosis were prominent in 78%, 62%, 56% and 54% cases respectively. Basement membrane deposit was prominent in 14%, while perivascular inflammation and plugging were both prominent in 40% cases each. Conclusion: Certain histological features are distinctive enough to render a reasonably accurate diagnosis of Cutaneous LE in most of the cases, and include epidermal atrophy, basal cell damage, collagen damage, periappendigeal inflammation and hyperkeratosis. Key words: , Cutaneous, Diagnosis, Microscopic features.

Introduction Materials and Methods Lupus erythematosus (LE) is a multisystem, This descriptive study was performed at characterized by the formation of Pathology Department of Pakistan Institute of Medical against various cellular constituents. Sciences. Duration of study was one year. The total Skin is one of the target organs invariably affected by number of cases was 50, selected through convenience the disease1 and cutaneous lesions make up 3 out of non-probability sampling. Patients were selected 11 criteria set by American College of regardless of age, sex or site of the lesion. All cases for diagnosing systemic lupus erythematosus; these with a clinical suspicion of cutaneous LE, in whom being malar , discoid lesions and photosensitivity2. skin biopsy was performed to confirm the diagnosis, Cutaneous lupus erythematosus refers to were included in this study. Also only those cases cutaneous lesions of LE, whether occurring exclusively were selected in whom DIF or serological tests were or as part of a .3 The diagnosis of not performed. Poorly processed slides with a lot of cutaneous LE requires clinicohistological data along artifacts were excluded from the study. All skin with direct immunofluoresecence (DIF) and biopsies with a high index of suspicion of cutaneous serological reactions. In Pakistan, however, due to LE were routinely processed and stained with restricted resources it is not possible to perform Hematoxylin and Eosin. The diagnosis was rendered serology and DIF in every case. in weekly Dermatopathology session held every The aim of this study was to find out the value Friday together with several dermatologists on multi- of individual histologic features that can help in head microscope attached with TV monitors. diagnosing cutaneous LE in the absence of DIF or Thorough histopathological and clinical correlation serology and hence facilitate patient care by making was carried out. Later all the slides were reviewed by a accurate diagnosis without resorting to expensive senior pathologist. A criterion was set for examining diagnostic modalities. each slide. 12 parameters were studied in each case

76 International Journal of Pathology; 2005; 3(2): 76-80 including Hyperkeratosis, , Keratin respectively. Basement membrane deposit was plugging, Epidermal atrophy, Acanthosis, Basal cell prominent in 14%, while both perivascular damage, Basement membrane deposit, Pigmentory inflammation and keratin plugging were seen incontinence, Extravasation of RBCs, Periappendigeal prominently in 40% cases each (Table 1) and Perivascular inflammation & Collagen damage. Each of these parameters was further graded into nil, mild and prominent depending upon the certainty Collagen damage 50 with which a particular feature was present. All the Perivascular inflammation 48 data was entered into SPSS and frequencies calculated. Results were presented in the form of tables and Periappendigeal inflammation 48 graphs. Extravasation of RBCs 26 Pigmentory incontinence 34 Results Basement membrane deposit 41 Hyperkeratosis, basal cell damage and Basal cell damage 50 collagen damage were present in all 50 (100%) cases Acanthosis 15 while epidermal atrophy was seen in 49 (98%) and Epidermal atrophy 49 periappendigeal and perivascular inflammation were Keratin plugging 44 seen in 48 (96%) cases each. The least frequent Parakeratosis 8 parameter was parakeratosis (16%) followed by acanthosis (30%) (Figure 1). Hyperkeratosis 50 The epidermal atrophy was prominent in 90 % 0204060 cases, while basal cell damage, collagen damage, periappendigeal inflammation and hyperkeratosis Fig. 1: Frequencies of Individual Microscopic were prominent in 78%, 62%, 56% and 54% cases Features

Table: 1: Gradation of Individual Microscopic Features into Nil, Mild and Prominent

Nil Mild Prominent Total

Hyperkeratosis 0 23 (46%) 27 (54%) 50 (100%)

Parakeratosis 42 (84%) 3 (6%) 5 (10%) 50 (100%)

Keratin plugging 6 (12%) 24 (48%) 20 (40%) 50 (100%)

Epidermal atrophy 1 (2%) 4 (8%) 45 (90%) 50 (100%)

Acanthosis 35 (70%) 11 (22%) 4 (8%) 50 (100%)

Basal cell damage 0 11 (22%) 39 (78%) 50 (100%)

Basement membrane deposit 9 (18%) 34 (68%) 7 (14%) 50 (100%)

Pigmentory incontinence 16 (32%) 22 (44%) 12 (24%) 50 (100%)

Extravasation of RBCs 24 (48%) 20 (40%) 6 (12%) 50 (100%)

Periappendigeal inflammation 2 (4%) 20 (40%) 28 (56%) 50 (100%)

Perivascular inflammation 2 (4%) 28 (56%) 20 (40%) 50 (100%)

Collagen damage 0 19 (38%) 31 (62%) 50 (100%)

77 International Journal of Pathology; 2005; 3(2): 76-80

that displays systemic, cutaneous or both systemic and cutaneous

manifestations. Skin is

one of the target organs invariably affected by the disease1 and cutaneous lesions make up 3 out of 11 criteria set by American College

of Rheumatology for

diagnosing systemic Fig. 2: Epidermal Atrophy and lupus erythematosus; Fig. 5: Basement Membrane Keratin Plugging these being malar rash, Deposit discoid lesions and and Pigmentory Incontinence photosensitivity2. Cutaneous lupus erythematosus (LE) refers to cutaneous lesions of LE, whether occurring exclusively or as part of a systemic disease.3 Over time several classifications have been proposed for cutaneous lupus erythematosus3-6. The

classification proposed Fig. 3: Epidermal Atrophy and by Sontheimer et al.,3 based on clinical Hyperkeratosis Fig. 6: Ropy Collagen morphology and

specific histologic findings of the disease is more accepted and divides Cutaneous LE into 3 main forms that is, Chronic Cutaneous LE (CCLE), Subacute Cutaneous LE (SCCLE) and Acute Cutaneous LE (ACLE). Gilliam however expanded this classification on the basis of Specific and Non- Specific clinical and histological features found in LE patients.7, 8 For every patient with cutaneous lesions of LE, an initial workup is mandatory to exclude the possibility of a systemic disease and should include a battery of blood tests, serologic studies, histology of the cutaneous lesions and direct immunofluoresecence. As far as the serologic tests are concerned, the titres of Anti-nuclear

antibody (ANA), anti-Ro (SSA)/La (SSB), and Anti-cardiolipin Fig. 4: Basal Cell antibody (ACL) are usually raised. Also there is false positive VDRL test for syphilis. Histologically, Acute Cutaneous LE (ACLE) in early Discussion stages shows non- specific features including papillary dermal Lupus erythematosus (LE) is an and perivascular lymphocytic infiltrate. However, in an autoimmune connective tissue disorder established case of ACLE, one usually finds epidermal atrophy,

78 International Journal of Pathology; 2005; 3(2): 76-80 liquefactive degeneration, and papillary shows similar histological features differing only in that there is dermal fibrinoid deposition. The most prominent epidermal atrophy, minimal or non-existent follicle common form of Chronic Cutaneous LE plugging or thickening of the basal membrane, and mild to moderate (CCLE) is mononuclear cell infiltrate, restricted to the superficial in Discoid LE (DLE) that histologically SCLE lesions. displays following features: Direct immunofluoresecence (DIF) is not absolute for 1) hyperkeratosis with follicular plugging; diagnosis of LE but is helpful when other diagnostic features are 2) thinning and flattening of the stratum absent. DIF detects IgG, IgM and complement deposition at Malpighi's, 3) hydropic degeneration of dermoepidermal junction. basal cells; The current study focuses on diagnosis of Cutaneous LE histologically when serology or DIF are not available. As these are expensive diagnostic modalities they cannot be resorted to in every case, so the objective was to outline a set of histological features that can help in diagnosing LE or at least can suggest a diagnosis of LE. Jerdan et al.13 compared the histopathologic findings of 77 biopsies from 63 cutaneous lupus erythematosus patients, and observed the following significant characteristics for a diagnosis of LE (Chronic form) that is hyperkeratosis, follicular plugging, thickening of the basement membrane and superficial and deep mononuclear inflammatory infiltrate. In another study carried out by Bangert et al.,14 hyperkeratosis, thickening of the basement membrane,

extensive follicular damage and dense lymphocyte infiltrate Fig. 7: Myxoid Degeneration of involving the deep dermis are more suggestive of DLE while Collagen changes in SCLE are quantitatively different from those found in DLE, and epidermal atrophy is an important feature. George PM et al15 reviewed 9 skin biopsies from 6 children with DLE, and found well developed epidermal changes in only three specimens. All nine samples showed basal cell vacuolization to some extent and moderate to heavy perivascular and periappendigeal inflammation. They concluded that histological changes are distinctive enough to diagnose cutaneous LE, although some cases may require clinicopathologic correlation. Our study of 50 cases however, shows that hyperkeratosis, basal cell damage and collagen damage were present in all 50 (100%) cases while epidermal atrophy was seen in 49 (98%) and periappendigeal and perivascular inflammation were seen in 48 (96%) cases each. The most prominent parameter that was seen in 90% of cases was epidermal atrophy followed by basal cell damage, collagen damage, periappendigeal inflammation and Fig. 8: Periappendigeal and hyperkeratosis that were prominent in 78%, 62%, 56% and 54% cases Perivascular Lymphocytic Infiltrate respectively. On the other basement membrane deposit was prominently seen in 14%, and both perivascular inflammation and 4) a predominantly lymphocytic infiltrate keratin plugging in 40% cases. An interesting finding was that of a along the dermo-epidermal junction, spectrum of collagen damage that varied from case to case, ranging around the hair follicles and eccrine ducts, from myxoid degeneration of collagen to ropy- noodle like collagen in an interstitial pattern;9 5) edema, to ultimately solar elastosis. vasodilatation and extravasation of red In a study carried out by Al-Suwaid AR et al16 that compared blood cells in the upper dermis.6 diagnostic value of DIF in 18 cases of clinically established cutaneous Basement membrane shows thickening. LE, found that DIF was positive in 72.7% and histopathology in 66%. Melanin containing melanophages are Combination of the two techniques yielded 83% positivity. Although also seen in upper dermis.4, 10-12 SCLE histopathology was positive or suggestive in all cases, DIF was negative in two cases of early cutaneous LE. They thus concluded

79 International Journal of Pathology; 2005; 3(2): 76-80 that although DIF is an extremely Proença et al.17 analyzed DIF in 69 patients with DLE and found to important diagnostic tool, it must be be positive in 58.33%, with a predominance of C1q (41.66%), IgG always used in conjunction with (33.33%), C3 (33.33%) and IgM (21.66%). David-Bajar et al.,18 in their histopathology and the combination of study of 11 patients of DLE and seven of SCLE, found differences in the two techniques gives best results. the distribution patterns of immunoglobulin bands. Deposits of IgA,

IgM, IgG and C3b were observed in particulate distribution at the dermo-epidermal junction in DLE lesions whereas in lesions of SCLE, IgG deposits were Conclusion shown in the of all patients (they were anti- From our study of 50 cases, having a high Ro/SSA positive); IgM was present in all seven clinical suspicion of cutaneous LE, we conclude that patients, with distribution to the dermo- epidermal certain histological features are distinctive enough to junction, the lower epidermis and upper dermis; render a reasonably accurate diagnosis of Cutaneous deposits of C3b in the dermo- epidermal junction were LE in most cases. Although hyperkeratosis, basal seen in five out the seven patients. The authors cell damage and collagen damage were present in concluded from these findings that DIF distribution all 50 cases; epidermal atrophy, basal cell damage, patterns in SCLE were decisively different from those collagen damage, periappendigeal inflammation and found in DLE. According to Nieboer19 the sensitivity hyperkeratosis had the most diagnostic significance, as of DIF-histopathology in combination was more than they were prominently present in 90 %, 78%, 62%, 56% either method used separately, albeit not statistically and 54% cases respectively. In a proper clinical setting significant. The author recommended that in cases these are quite reliable criteria. Of course serological of LE, histopathology and DIF be used for diagnosis studies including anti double stranded DNA tests may as well as PAS staining. be carried out when necessary and can be afforded by Our study highlights the spectrum of the patient. histopathological changes that are logically expected in LE. The damage to the basal cells is direct result of Anti DNA against basement membrane result in References vacuolization of the basal cells (Liquefaction degeneration). The damage to the vessels results in 1. Sontheimer RD. Clinical manifestations of cutaneous lupus erythematosus. In: Wallace DJ, Hahn BH. Dubois'lupus exudation of plasma proteins and occasionally red erythematosus. 1st ed. Pennsylvania: Lea & Febiger 1993; 285-301. blood cells affecting dermal collagen and epidermal 2. Sánchez NP, Peters MS, Winkelmann RK. The histopathology of lupus erythematosus . J Am Acad Dermatol. 1981: nourishment. The former would result in dermal 673-80. edema, mucinous damage to the collagen resulting in 3. Sontheimer RD, Rothfield N, Gilliam JN. Lupus erythematosus. In: Fitzpatrick TB, Eisen AZ, Wolff K, Austen KF, Golsmith LA, Katz SI. pasty or ropy collagen and the latter in epidermal Dermatology in general medicine. 1st ed. New York: MacGraw-Hill atrophy and hyperkeratosis. The swollen dermis is 1987; 1993-2009. 4. Bundick WR, Ellis FA. Lupus erythematosus: Classification, diagnostic expected to impinge upon hair ducts causing follicular and prognostic value of biopsis. Southern Med J 1951; 44:205-13. plugging. The weak collagen and swollen collagen is 5. Callen JP. Treatment of cutaneous lesions in patients with lupus erythematosus. Dermatol Clin 1994; 12:201-6. also expected to give rise to vascular telengiectasia. 6. Laman SD, Provost TT. Cutaneous manifestations of lupus As LE patients may develop light hypersensitivity erythematosus. Rheum Dis Clin N Am 1994; 20: 195-212. 7. Gilliam JN, Sontheimer RD. Skin manifestations of SLE. Clin Rheum and eczema like picture, occasionally one encounters Dis 1982 Apr; 8:207-18. acanthosis. This may mask or “balance” epidermal 8. Sontheimer RD, Provost TT. Lupus erythematosus. In: Wallace DJ, Hahn BH. Dubois'lupus erythematosus. 1st ed. Pennsylvania: Lea & atrophy. In our series basal cell damage (liquefaction Febiger 1993; 1-65. necrosis), hyperkeratosis and collagen damage were 9. Ellis FA, Bundick WR. Histology of lupus erythematosus. Arch Dermatol 1954; 70:311-24. seen in all cases and hence the presence of these 10. Millard LG, Rowell NR. Abnormal laboratory test results and their features provide a strong base for diagnosis of LE. relationship to prognosis in discoid lupus erythematosus. Arch Dermatol 1970; 115:1055-8. Absence of these features on the other hand should 11. Magro CM, Crowson AN, Harrist TJ. The use of antibody to C5b-9 raise suspicion over presence of LE. However in the subclassification of lupus erythematosus. Br J Dermatol 1996; 134:855-62. hyperkeratosis was only mild in 46% cases. On 12. Lever WF, Schaumburg-Lever G. Enfermedades del tejido conectivo. the contrary epidermal atrophy was present in Histopatologia de la piel. Buenos Aires: JP Lippincott 1988:417-40. 13. Jerdan MS, Hood AF, Moore GW, Callen JP. Histopathologic 98% cases and was prominent in 90% cases. Thus comparison of the subsets lupus erythematosus. Arch Dermatol 1990; epidermal atrophy becomes a very significant finding. 126:52-5. 14. Bangert JL, Freeman RG, Sontheimer RD, Gilliam JN. Subacute Periappendigeal inflammation was also prominently cutaneous lupus erythematosus and discoid lupus erythematosus: present in 56 % cases. comparative histopathologic findings. Arch Dermatol 1984; 120: 332-7.

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15. George PM, Hood AF, Rest EB. Histopathology and em lesões de lúpus eritematoso discóide. An Bras Dermatol 1985; of discoid lupus erythematosus in children. 60:303-6. Pediatr Dermatol 1996; 13:269-73. 18. David-Bajar KM, Bennion SD, DeSpain JD, Golitz LE, Lee LA. Clinical, 16. Al, Venkataram MN, Bhushnurmath SR. Cutaneous lupus histologic, and immunofluorescent distinctions between subacute erythematosus: comparison of direct immunofluorescence findings cutaneous lupus erythematosus and discoid lupus erythematosus. with histopathology. Int J Dermatol. 1995; 34: 480-2. J Invest Dermatol 1992; 99:251-7. 17. Proença NG, Machado ER, Paes RP,Bernardes MF. Reavaliação dos 19. Nieboer C. The reliability of immunofluorescence and histopathology resultados obtidos com a técnica de imunoflurescência direta in the diagnosis of discoid lupus erythematosis and . Br J Dermatol 1986; 116:189-98.

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